Alternative process for the purification of an intermediate in the synthesis of non-ionic x-ray contrast agents

ABSTRACT

Alternative continuous downstream processes for the production of 5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (“Compound A”) are described. Compound A is a key intermediate in the production of iodixanol and iohexol, which are two of the biggest commercially available non-ionic x-ray contrast media agents.

TECHNICAL FIELD

This invention relates generally to non-ionic X-ray contrast agents. Itfurther relates to an alternative process for the production of anintermediate used in the synthesis of non-ionic X-ray contrast agents.In particular, it relates to an alternative downstream process for theproduction of5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide(“Compound A”), a key intermediate in the production of iodixanol andiohexol, which are two of the biggest commercially available non-ionicx-ray contrast media agents.

BACKGROUND OF THE INVENTION

Non-ionic X-ray contrast agents constitute a very important class ofpharmaceutical compounds produced in large quantities.5-[N-(2,3-dihydroxypropyl)-acetamido]-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide(“iohexol”),5-[N-(2-hydroxy-3-methoxypropyl)acetamidol-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide(“iopentol”) and1,3-bis(acetamido)-N,N′-bis[3,5-bis(2,3-dihydroxypropyl-aminocarbonyl)-2,4,6-triiodophenyl]-2-hydroxypropane(“iodixanol”) are important examples of such compounds. They generallycontain one or two triiodinated benzene rings.

The industrial production of non-ionic X-ray contrast agents involves amultistep chemical synthesis. To reduce the cost of the final product,it is critical to optimize the yield in each step. Even a small increasein yield can lead to significant savings in a large scale production. Inparticular, iodine is one of the most expensive reagent in the process.It is thus especially important to obtain a high yield with fewby-products and minimal wastage for each synthetic intermediateinvolving an iodinated compound. Furthermore, improved purity of areaction intermediate, especially at the latter stage of synthesis, isessential in providing a final drug substance fulfilling regulatoryspecification such as those expressed on US Pharmacopeia. In addition toeconomic and regulatory concerns, the environmental impact of anindustrial process is becoming an increasingly significant considerationin the design and optimization of synthetic procedures.

One process by which iodixanol(1,3-bis(acetamido)-N,N′-bis[3,5-bis(2,3-dihydroxypropylaminocarbonyl)-2,4,6-triiodophenyl]-2-hydroxypropane)can be prepared is according to Scheme 1 below starting from5-nitroisophthalic acid. See also U.S. Pat. No. 6,974,882. As part ofthe established acetylation process, intermediate5-amino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide)(“Compound B”) is acetylated to give overacetylated5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide(“Compound A”). Subsequently overacetylated Compound A is deacetylatedto remove O-acetyl groups formed during the previous acetylationreaction to give Compound A. After deacetylation, Compound A can bepurified (e.g., by crystallization). The purified Compound A can then beisolated. The isolated Compound A can then be dried for storage or itmay be used directly in the production of iodixanol (e.g., dimerizationof Compound A in the presence of epichlorohydrin results in theformation of iodixanol).

Consequently, the conversion of Compound B to Compound A is a key andimportant step in the both the small-scale and industrial scaleproduction of iodixanol.

There exists a need for effective and efficient processes for theindustrial scale production of intermediates such as5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide(“Compound A”). The present invention, as described below, answers sucha need by providing alternative downstream semi-continuous processes forthe production of Compound A that gives a significant increase in yieldand significant reduction in energy consumption and process time.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates downstream continuous processing of the solutioncomprising crude Compound A resulting from the alternative acetylationprocess described herein and simple crystallization of5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide(“Compound A”).

FIG. 2 illustrates downstream continuous processing of the solutionafter deacetylation with alternative acetylation and no crystallizationand drying of5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide(“Compound A”).

SUMMARY OF THE INVENTION

The present invention provides an alternative process for theacetylation of5-amino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide)(“Compound B”) to form Compound A followed by an alternative continuousdownstream process for the production of5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide(“Compound A”) comprising precipitation, purification (e.g., aseparation system such as microfiltration or centrifuge, a membranefiltration system (e.g., nanofiltration system)), and drying.

The present invention provides an alternative process for theacetylation of5-amino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide)(“Compound B”) to form Compound A followed by an alternative continuousdownstream process for the production of5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide(“Compound A”) comprising a membrane filtration system (e.g.,nanofiltration system) without the need for crystallization and drying.

The present invention provides an alternative continuous downstreamprocess for the production of5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide(“Compound A”) comprising precipitation, purification (e.g., aseparation system such as microfiltration or centrifuge, a membranefiltration system (e.g., nanofiltration system)), and drying.

The present invention provides an alternative continuous downstreamprocess for the production of5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide(“Compound A”) comprising a membrane filtration system (e.g.,nanofiltration system) without the need for crystallization and drying.

The present invention provides a process comprising the steps of:

(i) reacting5-amino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide(“Compound B”) with a mixture of acetic anhydride/acetic acid to form afirst slurry;

(ii) heating said first slurry to about 60° C.;

(iii) adding an acid catalyst (preferably, para-toluene sulfonic acid(PTSA)) to said slurry at a rate such that the reaction temperature ismaintained at a temperature range of about 65-85° C.;

(iv) adding a deacetylating agent to the reaction mixture of step (iii)to form a reaction mixture comprising Compound A;

(v) purifying the reaction mixture of step (iv) comprising Compound Awherein said purifying step comprises the steps of:

(vi) passing said reaction mixture of step (iv) comprising Compound Athrough a separation system to create a second slurry and a liquid;

(vii) collecting the second slurry of step (vi) and repeating step (v);

(viii) collecting the liquid of step (vi) and passing it through amembrane filtration system;

(ix) collecting the retentate of step (viii) and repeating step (v); and

(x) continuously repeating steps (v)-(ix).

According to the process of the invention, the process may furthercomprise the step of: (xii) drying the reaction mixture of step (iv)comprising Compound A.

The present invention provides a process comprising the steps of:

(i) reacting5-amino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide(“Compound B”) with a mixture of acetic anhydride/acetic acid to form aslurry;

(ii) heating said slurry to about 60° C.;

(iii) adding an acid catalyst (preferably, para-toluene sulfonic acid(PTSA)) to said slurry at a rate such that the reaction temperature ismaintained at a temperature range of about 65-85° C.;

(iv) adding a deacetylating agent to the reaction mixture of step (iii)to form a reaction mixture comprising Compound A;

(v) purifying the reaction mixture of step (iv) comprising Compound Awherein said purifying step comprises the steps of:

(vi) passing said reaction mixture of step (iv) comprising Compound Athrough a membrane filtration system;

(vii) collecting the retentate of step (vi) and repeating step (v); and

(viii) continuously repeating steps (v)-(vii).

According to the process of the invention, the membrane filtrationsystem comprises a nanofiltration system as decribed herein.

According to the process of the invention, the process may furthercomprise the step of: alkylating the reaction mixture of step (iv)comprising Compound A.

According to the process of the invention, the process may furthercomprise the step of: bis-alkylating or dimerizing the reaction mixtureof step (iv) comprising Compound A.

DETAILED DESCRIPTION OF THE INVENTION

In the established industrial scale process, Compound B is added to amixture of acetic anhydride and acetic acid. The resulting slurry isthen heated to approximately 60° C. When the temperature is achieved, anacid catalyst (e.g., para-toluene sulfonic acid (PTSA)(s)) is added inone portion in catalytic amounts. Despite maximum cooling in the reactorjacket, the temperature of the reaction mixture increases rapidly toabout 120-125° C. due to the exothermic acetylation reaction. The mainpart of the acetylation reaction will accordingly occur at 120-125° C.Because of the high reaction temperature, considerable levels of thefollowing by-products I, II, and III in addition to Compound A areformed:

According to the present invention, an alternative acetylation processis provided. According to the present invention, Compound B is added toa mixture of acetic anhydride and acetic acid. The resulting slurry isthen heated to approximately 60° C. At this temperature, a catalyticamount of an acid catalyst is added. Examples of a suitable acidcatalyst include, for example, a sulfonic acid such as methanesulfonicacid, para-toluenesulfonic acid (PTSA) and sulphuric acid. Of these,para-toluenesulfonic acid (PTSA) is preferred. According to theinvention, the acid catalyst can be added as a solid or as a solution.Examples of suitable solvents to form such a solution include aceticacid, acetic anhydride or a mixture of acetic acid and acetic anhydride.The addition is performed carefully while the temperature is controlled.In one embodiment, the PTSA is added as a solid in several portions. Inone embodiment, the PTSA is added as a solution where PTSA is dissolvedin a small volume of acetic acid. In one embodiment, the PTSA is addedas a solution where PTSA is dissolved in a small volume of aceticanhydride. In one embodiment, the PTSA is added as a solution where PTSAis dissolved in a small volume of a mixture of acetic acid and aceticanhydride. The rate/speed of the addition of the acid catalyst,preferably PTSA, is such that the maximum reaction temperature ismaintained at about 65-85° C.

In a preferred embodiment, the rate/speed of the addition of the acidcatalyst, preferably PTSA, is such that the maximum reaction temperatureis maintained at about 70-80° C.

According to the present invention, addition of the acid catalyst,preferably PTSA, over time to control temperature produces a reactionmixture comprising overacetylated Compound A with lower levels ofby-products as described herein compared to the established acetylationprocess. The reaction mixture comprising overacetylated Compound A canthen be deacetylated using a deacetylating agent. There is no particularrestriction upon the nature of the deacylating agent used, and anydeacylating agent commonly used in conventional reactions may equally beused here. Examples of suitable deacylating agents include aqueousinorganic bases including alkali metal carbonates, such as sodiumcarbonate, potassium carbonate or lithium carbonate; and alkali metalhydroxides, such as sodium hydroxide, potassium hydroxide or lithiumhydroxide. Of these, the alkali metal hydroxides, particularly sodiumhydroxide or potassium hydroxide, and most preferably sodium hydroxideare preferred. For example, the reaction mixture comprisingoveracetylated Compound A can be deacetylated by the addition of base,such as sodium hydroxide, to form Compound A which in turn can then bepurified (e.g., crystallization) and isolated by techniques known in theart.

According to the invention, as a result of the alternative acetylationprocess described herein, the by-product profile is improved, whichmakes it possible to simplify the post deacetylation purification of the5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide(“Compound A”) and to isolate purified Compound A in higher yields.

As described above, by-products are formed during the acetylation of5-amino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide)(“Compound B”). In the established acetylation process, the by-productsthat form are at such a level that a crystallization step is necessaryto remove them from5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide(“Compound A”) prior to using Compound A in the synthesis of x-raycontrast media agents such as iodixanol and iohexol. If nocrystallization step is performed, then additional purification stepsneed to be included later in the process which results in moreproduction costs which is not ideal for industrial scale production.

It has now been found that the purity of5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide(“Compound A”) before crystallization measured as HPLC [area %] with theoriginal acetylation is 97.7% and with the alternative acetylationprocess described herein 99.2%. The alternative acetylation processreduces the formation of by-products.

In the alternative acetylation process, the process temperature isdecreased from about 115-125° C. to about 65-85° C. and the ratiobetween acetic anhydride and acetic acid in the process solution isreduced significantly as well. Table 1 summarizes the change inby-product profile and the corresponding HPLC [area %] between theoriginal and alternative acetylation process.

TABLE 1 By-products prior to crystallization with original andalternative acetylation Original Alternative acetylation acetylationprocess process Compound [HPLC area %] [HPLC area %] Compound A Purity97.7 99.2 Compound B remaining post acetylation 0.13 0.03 By-products Iand II 1.25 0.25 By-product III 0.33 0.01In the established acetylation process, salt by-products (e.g. sodiumchloride and sodium acetate) are removed from5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide(“Compound A”) during a crystallization and filtration step. pH andtemperature in solution is under strict control. Seeding to controlcrystallization is executed at a certain pH and temperature. The pH isadjusted to about 2.0-8.0, preferably about 5.0-8.0 and most preferablyabout 7. The temperature is maintained at about 10-25° C., preferablyabout 20° C. Then the crystallization process is allowed to run forapprox. 24 hours before the slurry is carefully transferred to apressure filter. On the pressure filter, the mother liquor is removed.Then the filter cake is carefully agitated before washing liquid isapplied. The filter cake is partly dried on the filter by blowing a hugeamount of hot gas through the cake. Total residence time on the pressurefilter is approx. 24 hours. Partly dried filter cake is then transferredto an indirect batch dryer. Dry5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide(“Compound A”) is then milled to destroy lumps generated during drying.

The present invention now provides two alternative continuouspurification processes that eliminate the need for the establishedcrystallization step. Each of the purification processes of the presentinvention can be used with either the established or alternativeacetylation process. In a preferred embodiment, each of the purificationprocesses is used subsequent to the alternative acetylation processdescribed herein.

It has now been found that purification of Compound A can be achieved byusing membrane filtration where low molecular weight by-products andsalts are collected in the permeate and5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide(“Compound A”) is collected in the retentate.

According to a process of the invention, the separation system can beany separation system capable of providing a liquid as particle free aspossible prior to passing the liquid through the membrane filtrationsystem, as described herein. In one embodiment of the invention, theseparation system comprises a microfiltration system (e.g., crossflowmicrofiltration). In one embodiment of the invention, the separationsystem comprises a centrifuge. According to the invention, anymicrofiltration system known in the art may be used. According to theinvention, any centrifuge capable of separating particles from theliquid may be used (e.g., a decanter centrifuge).

According to the invention, a suitable “membrane filtration system”includes any membrane filtration technique known in the art. In oneembodiment of the invention, the membrane filtration system comprises ananofiltration system. Any nanofiltration system known in the art may beused.

The alternative continuous downstream processes of the invention allowsfor an increase in the overall yield of5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide(“Compound A”), reduce process time and labour costs. The alternativecontinuous downstream processes of the invention further offer theadvantage of providing a stabilized process by removing a complex andmanual crystallization and isolation step used in the establishedacetylation process to form Compound A as described above.

Alternative Process 1:

Alternative process 1, exemplified in FIG. 1, includes a simpleprecipitation step to reduce pH and viscosity in the solution comprisingdesired Compound A. Particle size and distribution of5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide(“Compound A”) is not critical as it is in the established acetylationprocess because no filter cake is going to be handled.

After precipitation, the slurry can, if needed, be filtered using anappropriate particle-liquid separation technique known in the art (e.g.crossflow microfiltration or decanter centrifuge) to separate thereaction mixture into5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide(“Compound A”) solids (i.e. slurry) and liquid. The removed solids(i.e., slurry) are circulated back to the reactor. Removal of slurry isperformed to protect the membrane filtration system (e.g.,nanofiltration membrane) through which the liquid is passed and increaseits capacity.

The liquid from the separation system contains dissolved5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide(“Compound A”), salts and by-products. The liquid is then passed througha membrane filtration system (e.g., nanofiltration membrane of the crossflow type) that is resistant to methanol at neutral to acidic pH and hasa cut-off that allows the passing of low molecular weight by-products(<app. 300 dalton) or small molecules as salts to be collected inpermeate together with only small amounts of5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide(“Compound A”). The membrane filtration system (e.g., nanofiltrationmembrane) reduces5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide(“Compound A”) yield loss to a minimum as it is separated into theretentate while effectively removing by-products in the permeate. Theretentate produced by the membrane filtration system contains themajority of the5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide(“Compound A”) and is fed back into the reactor.

Any remaining salts and other low molecular weight by-products in theretentate can be removed with methanol, water, or a mixture thereof.Methanol, water, or a mixture thereof is added to reactor duringcirculation of the solution via the separation system and the membranefiltration system, each as described herein. Volume and pH in thereactor is monitored to keep suitable conditions for optimized membranefiltration. To further reduce the amount of by-products, parts of theliquid where by-products are concentrated, can optionally be removed asmother liquor from the system, see FIG. 1.

When the levels of salts and by-products have been achieved, the productslurry may be concentrated even more by stopping the methanol additioninto the reactor while the circulation of the solution via theseparation system and the membrane filtration system is still going.This alternative downstream process is performed continuously until thelevel of salts is not more than (NMT) 1.5 wt % and the level ofby-products is NMT 2.0 area % in the dry Compound A obtained.

Once Compound A has achieved a such a purity profile, it can be driedusing a continuous, direct dryer to give a lump free powder of5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide(“Compound A”) which can then be subsequently stored. According to theinvention, this alternative process 1 can be automated.

Alternative Process 2:

In Alternative process 2, as illustrated in FIG. 2, the crude reactionsolution after deacetylation is fed into a reactor and kept at pH>11 tokeep5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide(“Compound A”) dissolved. In order to prepare the solution for directlyuse in the syntheses of iohexol and iodixanol, the water in the solutionhas to be replaced by solvents such as methanol, which in turn canoptionally be replaced by 2-methoxyethanol in a nanofiltration systemwith a membrane with appropriate cut-off that withstands solvents andhigh pH. The salts and low molecular weight by-products are collected inthe permeate. 5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (“Compound A”) iscollected in the retentate. The use of a nanofiltration system allowsfor concentration adjustment of5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide(“Compound A”) before being fed back into the reactor. By adjusting theconcentration and process time, production capacity and investmentscost/operational costs can be optimized. Alternative process 2 iscontinuous until the level of salts is NMT 1.5 wt % and the level ofby-products is NMT 2.0 area % in the Compound A solution.

Once such a purity profile of Compound A is achieved, then the CompoundA can be directly used to synthesize x-ray contrast media agents such asiohexol and iodixanol via alkylation and bis-alkylation (dimerization)respectively. Alternative process 2 eliminates the need for a dryingstep as used in the established process and in alternative process 1.Since the drying step can be eliminated, Alternative process 2 alsooffers the advantage of the need for storage of Compound A. According tothe invention, this alternative process 2 can be automated.

As illustrated in Table 2, Alternative process 1 and Alternative process2, provide comparable quality and yields as compared to the establishedoriginal process. In addition, the processes offer the advantage ofimproved energy savings and reduction in overall production time.

TABLE 2 Changes in key parameters in the modified processes AlternativeAlternative Original process process 1 process 2 Compound A Purity 99.5%99.2-99.5% Ca. 99.2% Yield 96.2% 97-99% 99.2% Energy savings* — MuchVery much Reduction of process — Ca. 25% >60% time* *as compared to thealready established process.

1. A process comprising the steps of: (i) reacting5-amino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide(“Compound B”) with a mixture of acetic anhydride/acetic acid to form afirst slurry; (ii) heating said first slurry to about 60° C.; (iii)adding an acid catalyst to said slurry at a rate such that the reactiontemperature is maintained at a temperature range of about 65-85° C.;(iv) adding a deacetylating agent to the reaction mixture of step (iii)to form a reaction mixture comprising Compound A; (v) purifying thereaction mixture of step (iv) comprising Compound A wherein saidpurifying step comprises the steps of: (vi) passing said reactionmixture of step (iv) comprising Compound A through a separation systemto form a second slurry and liquid; (vii) collecting the second slurryof step (vi) and repeating step (v); (viii) collecting the liquid ofstep (vi) and passing it through a membrane filtration system; (ix)collecting the retentate of step (viii) and repeating step (v); and (x)continuously repeating steps (v)-(ix).
 2. The process according to claim1, wherein said separation system comprises a microfiltration system ora decanter centrifuge.
 3. The process according to claim 1, wherein saidmembrane filtration system comprises a nanofiltration system.
 4. Theprocess according to claim 1, wherein said separation system comprises amicrofiltration system or a decanter centrifuge and said membranefiltration system comprises a nanofiltration system.
 5. The processaccording to claim 1, wherein step (x) is repeated until the level ofsalts is not more than (NMT) 1.5 wt % and the level of by-products isNMT 2.0 area % in the dry Compound A obtained.
 6. The process accordingto claim 1, further comprising the step of: drying the reaction mixtureof step (iv) comprising Compound A.
 7. The process according to claim 5,further comprising the step of: drying the reaction mixture of step (iv)comprising Compound A.
 8. The process according to claim 1 wherein saidacid catalyst is a sulfonic acid.
 9. The process according to claim 8,wherein said acid catalyst is a para-toluene sulfonic acid (PTSA). 10.The process according to claim 9, wherein said PTSA is added in acatalytic amount as a solid.
 11. The process according to claim 9,wherein said PTSA is added in a catalytic amount as a solution of PTSAdissolved in a small volume of acetic anhydride.